Sialic acid contains a net negative charge and is found on terminating branches of glycans, which include glycoproteins (with N- or O-linked glycosylation) and glycolipids (including glycosphingolipids or gangliosides). The sialic acid modification of cell surface molecules impacts protein structure and stability, regulation of cell adhesion, and signal transduction, amongst other processes.
Clinical diseases with a reduced amount of sialic acid bound to glycans are called “hyposialylation disorders.” Hyposialylation can occur in a specific tissue or can be systemic. In some cases genetic defects cause hyposialylation disorders, but the etiology of many of these disorders is unknown.
One hyposialylation disorder associated with a genetic defect is GNE myopathy (also called HIBM, IBM type 2, Nonaka myopathy, or Distal Myopathy with Rimmed Vacuoles (DMRV)). GNE myopathy is caused by mutations in the GNE gene, encoding the key enzyme in sialic acid synthesis, the bifunctional enzyme UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. Decreased GNE enzyme activity is believed to reduce sialic acid levels.
Other genetic disorders that may involve sialylation defects are the congenital disorders of glycosylation (CDGs). CDGs are a group of human genetic disorders characterized by alterations in glycoconjugates (Jaeken, J Inherit Metab Dis 2011, 34:853-858). A majority of the CDGs are caused by primary defects in the N- and/or O-glycosylation pathways that lead to defective glycan biosynthesis. In the past decade, about 60 genetic diseases have been identified that alter glycan synthesis and structure and ultimately the functions of many organ systems (He et al., The congenital disorders of glycosylation. In: Laboratory Diagnosis of inherited Metabolic Diseases. edn. Edited by Garg et al., Washington, D.C.: AACC Press; 2012: 179-199). CDG type I (CDG-I) disorders result from impaired synthesis of glycans, which may lead to unoccupied glycosylation sites on glycoproteins and glycolipids. CDG type II (CDG-II) disorders result from impaired processing of glycans, which lead to accumulation of glycoproteins and glycolipids with abnormal structures. CDG-II disorders also includes defects in chaperones and Golgi-trafficking complexes, such as defects in the conserved oligomeric Golgi complex (COG), dolichol synthesis, and CMP-sialic acid synthesis, which impair multiple glycosylation pathways including both N- and O-glycan synthesis and N-glycan processing (He et al., supra). Some multiple glycosylation defects may also present as mixed CDG-I and II (Pérez et al., JIMD, epub 2012; Perez et al., JIMD 2011, 1: 117-123; Mandato et al., Pediatr Res 2006, 59(2):293-298).
There is a need for non-invasive methods for the diagnosis of glycosylation disorders, including hyposialylation disorders, such as GNE myopathy and CDG disorders, and methods to determine the effectiveness of therapeutic agents for the treatment of hyposialylation disorders.